DESCRIPTION: Myotonic dystrophy 1 (DM1) is the leading form of adult muscular dystrophy resulting in progressive neuromuscular effects. The disease affects 1 in 6000 people. Nymirum is interested in identifying a small molecule that can be used to slow or eliminate the progression of DM1. The cause of DM1 is the expansion of a CUG RNA sequence within the DMPK gene. This repeat RNA is toxic to normal cellular function by sequestering and altering the activity of needed splicing factors for normal neuromuscular function. We are taking an approach to identify small molecules that will bind to the expanded CUG RNA repeat to prevent sequestration of splicing factors and repair the abnormal splicing phonotype in cells. To this end we have identified 2 chemical series of small molecules with clear structure activity relationships for CUG RNA binding and rescue of abnormal splicing in a DM1 cell model. In this proposal, we aim to optimize the structural features of the series to find more potent binders and splicing rescue molecules. To do this we will utilize our extensive knowledge and tools related to RNA structure and small molecule interactions and bring it to bear on targeted medicinal chemistry. DM1 represents a major unmet medical need and patients are in need of new drugs to slow or eliminate the neuromuscular deterioration